Guide to Good Facility Design

This Guide is not intended to be an architectural guide-the author is a biopharmaceutical and regulatory compliance consultant, not an architect. Rather, it is intended to assist the scientific and managerial staff of biological and pharmaceutical companies to understand the requirements and constraints that are placed by the regulatory agencies upon the design of laboratory and manufacturing plant layouts, their modes of construction and finishing, and the specifications of the key systems therein. It will enable non-specialists to participate effectively in the planning process and discuss their needs sensibly with architects and contractors. The drug regulatory agencies' requirements for pharmaceutical and biopharmaceutical establishments to comply with such practices are found mostly in the Good Laboratory Practice and Good Manufacturing Practice regulations. This Guide examines these regulations and details the means whereby a facility design that is in compliance with them can be achieved economically and efficiently.

Good Laboratory Practice regulations define laboratories that must be compliant as those which perform the characterization of a drug product or the testing of its safety, efficacy or potency. The emphasis in GLP operations is the need to avoid contamination or a mix-up of the test samples and to prevent any compromise of the test procedures, by adequate separation of activities. The GMP principle to be applied to manufacturing facilities is that premises and equipment must be located, designed, constructed, adapted, and maintained to suit the operations to be carried out.

Their layout and design must aim to minimize the risk of errors and permit effective cleaning and maintenance in order to avoid cross-contamination, build up of dust or dirt, and, in general, any adverse effect on the quality of products.

Beyond this requirement to ensure the quality of the product stands the equal necessity to minimize all risks to the personnel in the plant and the public in general, from any hazardous materials that may be handled in the plant. The Health and Safety and Environmental Protection agencies of most countries have laid down additional rules which deal with this second need.

From the design point of view, the simple rule of "Nothing extraneous in, nothing hazardous out" can be used to meet both problems.

Therefore, there are certain factors in the design of biological and pharmaceutical facilities that are common to all facility types. These deal with cleanliness, logical workflow, adequate space, and the proper separation of processes and functions. Good design and construction will prevent the entry of dirt, vermin, insects, etc. into the facility and will allow for the easy removal of dust and dirt from all interior surfaces. There should be a logical progression from the dirtiest to the cleanest sections of the facility, with means to prevent carry-over of contamination.

The intention of regulations emphasizing the use of a logical flow of materials through the laboratory or plant is to reduce the chance of sample or product contamination or mix-up to a minimum. This has particular application to product development and testing laboratories, and to plants in which different products are produced simultaneously, or biological facilities where living organisms are handled, as well as noninfectious preparations. Adequate separation of different processes and functions is a key factor in all plant design. Without adequate separation, it will not be possible to obtain agreement from regulatory inspectors that the plant can comply with GLP/GMP requirements. In fact, it may not actually be possible to validate certain processes such as the cleaning of process-dedicated areas - another regulatory requirement, unless they are adequately segregated. Several facility layouts illustrating ways of meeting this need are given in the text.

Certain design factor requirements are more specific to biopharmaceutical or other parenteral product facilities. These are dealt with in additional detail. They include the supply of purified air and process water, steam and gases; the requirement for the complete isolation and control of chemical and biological hazards in the plant; the need to prevent and control microbiological contamination of parenteral and other aseptic products; and the special needs of animal facility design.

The primary task of the HVAC system is to maintain preset environmental conditions in every part of the plant. This requires adequate control of temperature and humidity and needs to provide sufficient air changes to ensure the comfort of the occupants and no buildup of toxic or hazardous gases. Beyond that, however, the quality and movement of air through the various sections of the facility can assist in the control of cross-contamination. This is where design of the HVAC system has GMP significance.

Most pharmaceutical processes require water with higher levels of purity than drinking water.

The most common grades are defined in the United States Pharmacopoeia standard as "Purified Water", or "Water for Injection", the latter being mandatory for all parenteral products. Water for Injection systems require specific standards of pipework layout and water circulation which are all defined in the text. Similar layouts are described for systems supplying pure steam to bioreactors and autoclaves.

Special attention is paid to the design factors involved in the containment of biohazardous organisms. The four official levels of containment are described, with the construction and air supply needs that each level generates. There are specific types of biohazard cabinets that are defined for each level. These are illustrated in the text. The biohazard precautions can be incorporated into cleanroom systems, which will also provide the required level of air purity for each stage of biopharmaceutical manufacture. Similar arrangements can be made for animal facilities which may be handling infectious organisms. This topic is illustrated with floor plans and building sectional drawings.

The critical information to be assembled before formal design is started must include the relationship between form and function in the facility, past experience in facility design, and the economics of the project. The key elements of form and function can be defined by the use of bubble diagrams, which are illustrated in the text. Actual floor plans derived from the use of such diagrams are also shown.

Supporting chapters define the purity standards that are to be applied to cleanroom air and purified water supplies, as well as the biohazard classification of micro-organisms that may be handled in laboratories and plants. The Guide concludes with abstracts from all relevant regulations and sources for further information, including government guidelines and other useful publications.

The best indication of the attention that is being paid to the compliance of facilities with GLP/GMP regulations is to be found in the warning letters issued by the FDA (USA) following the inspection of the facilities. Normally, a warning letter is only issued when the Agency is concerned that serious non-compliance issues reported by the inspectors at the end of the inspection visit, in the FDA Form 483, have not been adequately addressed by the firm. The topics of building layout, the separation of functions and systems operation, maintenance, and validation appear regularly in the lists of citations. This guide is intended to reduce the risk of such citation to a minimum.